Cocaine dependence is a problem of national significance. To date no cocaine pharmacotherapy has been reported. Cocaine is a potent stimulant of the mammalian central nervous system. Its reinforcing properties and stimulant effects are associated with its propensity to bind to monoamine transporters, particularly the dopamine transporter (DAT). (Kennedy, L. T. and I. Hanbauer (1983), J. Neurochem. 34: 1137-1144; Kuhar, M. J., M. C. Ritz and J. W. Boja (1991), Trends Neurosci. 14: 299-302; Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R. D. Spealman (1989), J. Pharmacol. Exp. Ther. 251: 131-141; Madras, B. K., J. B. Kamien, M. Fahey, D. Canfield, et al. (1990), Pharmacol Biochem. Behav. 35: 949-953; Reith, M. E. A., B. E. Meisler, H. Sershen and A. Lajtha (1986), Biochem. Pharmacol. 35: 1123-1129; Ritz, M. C., R. J. Lamb, S. R. Goldberg and M. J. Kuhar (1987), Science 237: 1219-1223; Schoemaker, H., C. Pimoule, S. Arbilla, B. Scatton, F. Javoy-Agid and S. Z. Langer (1985), Naunyn-Schmiedeberg's Arch. Pharmacol. 329: 227-235.) It also binds with substantial potency to serotonin transporters (SERT) and norepinephrine transporters.
Structure activity relationship (SAR) studies have largely focused on a series of cocaine analogs. Among the more potent of these congeners at .sup.3 H-cocaine binding sites in striatum (Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R. D. Spealman (1989), J. Pharmacol. Exp. Ther. 251: 131-141; Reith, M. E. A., B. E. Meisler, H. Sershen and A. Lajtha (1986), Biochem. Pharmacol. 35: 1123-1129) is (1R)-3.beta.-(4-fluorophenyl)tropane-2.beta.-carboxylic acid methyl ester, (WIN35,428 or CFT) (Kaufman, M. J. and B. K. Madras (1992), Synapse 12: 99-111; Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R. D. Spealman (1989), J. Pharmacol. Exp. Ther. 251: 131-141) reported in 1973 (Clarke, R. L., S. J. Daum, A. J. Gambino, M. D. Aceto, et al. (1973), J. Med. Chem. 16: 1260-1267). This compound was subsequently radiolabeled to provide a selective probe for the DAT in primate brain. (Canfield, D. R., R. D. Spealman, M. J. Kaufman and B. K. Madras (1990), Synapse 6: 189-195; Kaufman, M. J. and B. K. Madras (1991), Synapse 9: 43-49; Kaufman, M. J., R. D. Spealman and B. K. Madras (1991), Synapse 9: 177-187.)
Among the most potent tropane inhibitors of monoamine binding sites in striatum are 3.beta.-{4-(1-methylethenyl)phenyl}-2.beta.-propanoyl-8-azabicyclo(3.2. 1)octane, (Bennett, B. A., C. H. Wichems, C. K. Hollingsworth, H. M. L. Davies, C. Thornley, T. Sexton and S. R. Childers (1995), J. Pharm. Exp. Ther. 272: 1176-1186; Davies, H. M. L., L. A. Kuhn, C. Thornley, J. J. Matasi, T. Sexton and S. R. Childers (1996), J. Med. Chem. 39: 2554-2558) (1R)-RTI55 (.beta.CIT), (Boja 1991; Boja, J. W., A. Patel, F. I. Carroll, M. A. Rahman, et al. (1991), Eur. J. Pharmacol. 194: 133-134; Neumeyer, J. L., S. Wang, R. A. Milius, R. M. Baldwin, et al. (1991), J. Med. Chem. 34: 3144-3146) (1R)-RTI121, (Carroll, F. I., A. H. Lewin, J. W. Boja and M. J. Kuhar (1992), J. Med. Chem. 35: 969-981.) and (1R)-3.beta.-(3,4-dichlorophenyl)-tropane-2.beta.-carboxylic acid methyl ester (O-401), (Carroll, F. I., M. A. Kuzemko and Y. Gao (1992), Med. Chem Res. 1: 382-387; Meltzer, P. C., A. Y. Liang, A.-L. Brownell, D. R. Elmaleh and B. K. Madras (1993), J. Med. Chem. 36: 855-862).
SAR studies of the binding of these agents and their effects on monoamine transporter function have been reported. (Blough, B. E., P. Abraham, A. H. Lewin, M. J. Kuhar, J. W. Boja and F. I. Carroll (1996), J. Med. Chem. 39: 4027-4035; Carroll, F. I., P. Kotian, A. Dehghani, J. L. Gray, et al. (1995), J. Med. Chem. 38: 379-388; Carroll, F. I., A. H. Lewin, J. W. Boja and M. J. Kuhar (1992),y J. Med. Chem. 35: 969-981; Carroll, F. I., S. W. Mascarella, M. A. Kuzemko, Y. Gao, et al. (1994), J. Med. Chem. 37: 2865-2873; Chen, Z., S. Izenwasser, J. L. Katz, N. Zhu, C. L. Klein and M. L. Trudell (1996), J. Med. Chem. 39: 4744-4749; Davies, H. M. L., L. A. Kuhn, C. Thornley, J. J. Matasi, T. Sexton and S. R. Childers (1996), J. Med. Chem. 39: 2554-2558; Davies, H. M. L., Z.-Q. Peng and J. H. Houser (1994), Tetrahedron Lett. 48: 8939-8942; Davies, H. M. L., E. Saikali, T. Sexton and S. R. Childers (1993), Eur. J. Pharmacol. Mol. Pharm. 244: 93-97; Holmquist, C. R., K. I. Keverline-Frantz, P. Abraham, J. W. Boja, M. J. Kuhar and F. I. Carroll (1996), J. Med. Chem 39: 4139-4141; Kozikowski, A. P., G. L. Araldi and R. G. Ball (1997), J. Org. Chem. 62: 503-509; Kozikowski, A. P., M. Roberti, L. Xiang, J. S. Bergmann, P. M. Callahan, K. A. Cunningham and K. M. Johnson (1992), J. Med. Chem. 35: 4764-4766; Kozikowski, A. P., D. Simoni, S. Manfredini, M. Roberti and J. Stoelwinder (1996), Tetrahedron Lett. 37: 5333-5336; Meltzer, P. C., A. Y. Liang, A.-L. Brownell, D. R. Elmaleh and B. K. Madras (1993), J. Med. Chem. 36: 855-862; Meltzer, P. C., A. Y. Liang and B. K. Madras (1994), J. Med. Chem. 37: 2001-2010; Meltzer, P. C., A. Y. Liang and B. K. Madras (1996), J. Med. Chem. 39: 371-379; Newman, A. H., A. C. Allen, S. Izenwasser and J. L. Katz (1994), J. Med Chem. 37: 2258-2261; Newman, A. H., R. H. Kline, A. C. Allen, S. Izenwasser, C. George and J. L. Katz (1995), J. Med. Chem. 38: 3933-3940; Shreekrishna, V. K., S. Izenwasser, J. L. Katz, C. L. Klein, N. Zhu and M. L. Trudell (1994), J. Med. Chem. 37: 3875-3877; Simoni, D., J. Stoelwinder, A. P. Kozikowski, K. M. Johnson, J. S. Bergmann and R. G. Ball (1993), J. Med. Chem. 36: 3975-3977.)
Binding of cocaine and its tropane analogs to monoamine transporters is stereoselective. As example (1R)-(-)-cocaine binds at the dopamine transporter about 200-fold more potently than the unnatural isomer, (1S)-(+)-cocaine. (Kaufman, M. J. and B. K. Madras (1992), Synapse 12: 99-111; Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R. D. Spealman (1989), J. Pharmacol. Exp. Ther. 251: 131-141; Madras, B. K., R. D. Spealman, M. A. Fahey, J. L. Neumeyer, J. K. Saha and R. A. Milius (1989), Mol. Pharmacol. 36: 518-524; Reith, M. E. A., B. E. Meisler, H. Sershen and A. Lajtha (1986), Biochem. Pharmacol. 35: 1123-1129; Ritz, M. C., R. J. Lamb, S. R. Goldberg and M. J. Kuhar (1987), Science 237: 1219-1223.)
Also, only the R-enantiomers of cocaine have been found active in a variety of biological and neurochemical measures. (Clarke, R. L., S. J. Daum, A. J. Gambino, M. D. Aceto, et al. (1973), J. Med. Chem. 16: 1260-1267; Kaufman, M. J. and B. K. Madras (1992), Synapse 12: 99-111; Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R. D. Spealman (1989), J. Pharmacol. Exp. Ther. 251: 131-141; Madras, B. K., R. D. Spealman, M. A. Fahey, J. L. Neumeyer, J. K. Saha and R. A. Milius (1989), Mol. Pharmacol. 36: 518-524; Reith, M. E. A., B. E. Meisler, H. Sershen and A. Lajtha (1986), Biochem. Pharmacol. 35: 1123-1129; Ritz, M. C., R. J. Lamb, S. R. Goldberg and M. J. Kuhar (1987), Science 237: 1219-1223; Sershen, H., M. E. A. Reith and A. Lajtha (1980), Neuropharmacology 19: 1145-1148; Sershen, H., M. E. A. Reith and A. Lajtha (1982), Neuropharmacology 21: 469-474; Spealman, R. D., R. T. Kelleher and S. R. Goldberg (1983), J. Pharmacol. Exp. Ther. 225: 509-513.) Parallel stereoselective behavioral effects have also been observed. (Bergman, J., B. K. Madras, S. E. Johnson and R. D. Spealman (1989), J. Pharmacol. Exp. Ther. 251: 150-155; Heikkila, R. E., L. Manzino and F. S. Cabbat (1981), Subst. Alcohol Actions/Misuse 2: 115-121; Reith, M. E. A., B. E. Meisler, H. Sershen and A. Lajtha (1986), Biochem. Pharmacol. 35: 1123-1129; Spealman, R. D., R. T. Kelleher and S. R. Goldberg (1983), J. Pharmacol. Exp. Ther. 225: 509-513; Wang, S., Y. Gai, M. Laruelle, R. M. Baldwin, B. E. Scanlet, R. B. Innis and J. L. Neumeyer (1993), J. Med. Chem. 36: 1914-1917.) For example, in primates and rodents the stimulating and reinforcing properties of the (-)-enantiomer of cocaine or its 3-aryltropane analogs were considerably greater than for the (+)-enantiomers.
Although SAR studies of cocaine and its 3-aryltropane analogs have offered insight into their mode of binding to monoamine transporters, a comprehensive picture of the binding interaction at the molecular level has not emerged. SAR studies on the classical tropane analogs (Carroll, F. I., Y. Gao, M. A. Rahman, P. Abraham, et al. (1991), J. Med. Chem. 34: 2719-2725; Carroll, F. I., S. W. Mascarella, M. A. Kuzemko, Y. Gao, et al. (1994), J. Med. Chem. 37: 2865-2873; Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R. D. Spealman (1989), J. Pharmacol. Exp. Ther. 251: 131-141; Madras, B. K., R. D. Spealman, M. A. Fahey, J. L. Neumeyer, J. K. Saha and R. A. Milius (1989), Mol. Pharmacol. 36: 518-524; Meltzer, P. C., A. Y. Liang, A.-L. Brownell, D. R. Elmaleh and B. K. Madras (1993), J. Med. Chem. 36: 855-862; Reith, M. E. A., B. E. Meisler, H. Sershen and A. Lajtha (1986), Biochem. Pharmacol. 35: 1123-1129) appeared to provide a consistent model for this interaction with the DAT, however, subsequent studies revealed inconsistencies. (Carroll, F. I., P. Kotian, A. Dehghani, J. L. Gray, et al. (1995), J. Med. Chem. 38: 379-388; Chen, Z., S. Izenwasser, J. L. Katz, N. Zhu, C. L. Klein and M. L. Trudell (1996), J. Med. Chem. 39: 4744-4749; Davies, H. M. L., L. A. Kuhn, C. Thornley, J. J. Matasi, T. Sexton and S. R. Childers (1996), J. Med. Chem. 39: 2554-2558; Kozikowski, A. P., G. L. Araldi and R. G. Ball (1997), J. Org. Chem. 62: 503-509; Meltzer, P. C., A. Y. Liang and B. K. Madras (1994), J. Med. Chem. 37: 2001-2010; Meltzer, P. C., A. Y. Liang and B. K. Madras (1996), J. Med. Chem. 39: 371-379.)
Carroll had proposed (Boja, J. W., R. M. McNeill, A. Lewin, P. Abraham, F. I. Carroll and M. J. Kuhar (1992), Mol. Neurosci. 3: 984-986; Carroll, F. I., P. Abraham, A. Lewin, K. A. Parham, J. W. Boja and M. J. Kuhar (1992), J. Med. Chem. 35: 2497-2500; Carroll, F. I., Y. Gao, M. A. Rahman, P. Abraham, et al. (1991), J. Med. Chem. 34: 2719-2725; Carroll, F. I., M. A. Kuzemko and Y. Gao (1992), Med. Chem Res. 1: 382-387) four molecular requirements for binding of cocaine and its tropane analogs at the DAT: a 2.beta.-carboxy ester, a basic nitrogen capable of protonation at physiological pH, the R-configuration of the tropane and a 3.beta.-aromatic ring at C.sub.3. However, Davies (Davies, H. M. L., E. Saikali, T. Sexton and S. R. Childers (1993), Eur. J. Pharmacol. Mol. Pharm. 244: 93-97) later reported that introduction of 2.beta.-ketones did not reduce potency. Kozikowski questioned the role of hydrogen bonding at the C.sub.2 site because introduction of unsaturated and saturated alkyl groups (Kozikowski, A. P., M. Roberti, K. M. Johnson, J. S. Bergmann and R. G. Ball (1993), Bioorg. Med. Chem. Lett. 3: 1327-1332; Kozikowski, A. P., M. Roberti, L. Xiang, J. S. Bergmann, P. M. Callahan, K. A. Cunningham and K. M. Johnson (1992), J. Med. Chem. 35: 4764-4766) did not diminish binding. Further, the ionic bond between a protonated amine (at physiologically pH) and the presumed (Kitayama, S., S. Shimada, H. Xu, L. Markham, D. H. Donovan and G. R. Uhl (1993), Proc. Natl. Acad. Sci. U.S.A. 89: 7782-7785) aspartate residue on the DAT was questioned because reduction of nitrogen nucleophilicity (Kozikowski, A. P., M. K. E. Saiah, J. S. Bergmann and K. M. Johnson (1994), J. Med. Chem. 37(37): 3440-3442) by introduction of N-sulfones did not reduce binding potency.
It also has been reported (Madras, B. K., J. B. Kamien, M. Fahey, D. Canfield, et al. (1996), Pharmacol Biochem. Behav. 35: 949-953) that introduction of an alkyl or allyl group did not eliminate binding potency. An N-iodoallyl group on the tropane has provided potent and selective ligands for the DAT, and altropane is currently being developed as a SPECT imaging agent (Elmaleh, D. R., B. K. Madras, T. M. Shoup, C. Byon, et al. (1995), J. Nucl. Chem., 37 1197-1202 (1966); Fischman, A. J., A. A. Bonab, J. W. Babich, N. M. Alpert, et al. (1996), Neuroscience-Net 1, 00010, (1997). A .sup.99m technetium labeled compound, technepine, which binds potently and selectively to the DAT and provides excellent in vivo SPECT images has been reported. (Madras, B. K., A. G. Jones, A. Mahmood, R. E. Zimmerman, et al. (1996), Synapse 22: 239-246.) (Meltzer, P. C., Blundell, P., Jones, A. G., Mahmood, A., Garada, B. et al., J. Med. Chem., 40, 1835-1844, (1997). 2-Carbomethoxy-3-(bis(4-fluorophenyl)methoxy)tropanes have been reported (Meltzer, P. C., A. Y. Liang and B. K. Madras (1994), J. Med. Chem. 37: 2001-2010). The S-enantiomer, (S)-(+)-2.beta.-carbomethoxy-3.alpha.-(bis(4-fluorophenyl)methoxy)tropane (Difluoropine) was considerably more potent (IC.sub.50 : 10.9 nM) and selective (DAT v. SERT: 324) than any of the other seven isomers, including the R-enantiomers.
Drug therapies for cocaine abuse are needed. Also, there is a need for protective agents for neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease as well as therapeutic agents for dopamine related dysfunction such as Attention Deficit Disorder. Compounds that inhibit monoamine reuptake in the mammalian system are sought to provide such therapies.
Inhibition of 5-hydroxytryptamine reuptake has an effect on diseases mediated by 5HT receptors. Compounds that provide such inhibition can be useful, for example, as therapeutic anti-depressants.
Cocaine recognition sites are localized on monoamine transporters such as, for example, the dopamine transporter (DAT) and serotonin transporter (SERT). These transporters are localized, in turn, on monoamine nerve terminals. Compounds that bind to these sites can be useful as (i) probes for neuro-degenerative diseases (e.g., Parkinson's disease), (ii) therapeutic drugs for neurodegenerative diseases (e.g., Parkinson's and Alzheimer's disease), (iii) therapeutic drugs for dopamine dysfunction (e.g., Attention Deficit Disorder), (iv) treatment of psychiatric dysfunction (e.g., depression) and (v) treatment of clinical dysfunction (e.g., migraine).